Lower-extremity muscle activity during aquatic and land treadmill running at the same speeds.

CONTEXT: Muscle activation during aquatic treadmill (ATM) running has not been examined, despite similar investigations for other modes of aquatic locomotion and increased interest in ATM running. OBJECTIVES: The objectives of this study were to compare normalized (percentage of maximal voluntary contraction; %MVC), absolute duration (aDUR), and total (tACT) lower-extremity muscle activity during land treadmill (TM) and ATM running at the same speeds. DESIGN: Exploratory, quasi-experimental, crossover design. SETTING: Athletic training facility. PARTICIPANTS: 12 healthy recreational runners (age = 25.8 ± 5 y, height = 178.4 ± 8.2 cm, mass = 71.5 ± 11.5 kg, running experience = 8.2 ± 5.3 y) volunteered for participation. INTERVENTION: All participants performed TM and ATM running at 174.4, 201.2, and 228.0 m/min while surface electromyographic data were collected from the vastus medialis, rectus femoris, gastrocnemius, tibialis anterior, and biceps femoris. MAIN OUTCOME MEASURES: For each muscle, a 2 × 3 repeated-measures ANOVA was used to analyze the main effects and environment-speed interaction (P ≤ .05) of each dependent variable: %MVC, aDUR, and tACT. RESULTS: Compared with TM, ATM elicited significantly reduced %MVC (-44.0%) but increased aDUR (+213.1%) and tACT (+41.9%) in the vastus medialis, increased %MVC (+48.7%) and aDUR (+128.1%) in the rectus femoris during swing phase, reduced %MVC (-26.9%) and tACT (-40.1%) in the gastrocnemius, increased aDUR (+33.1%) and tACT (+35.7%) in the tibialis anterior, and increased aDUR (+41.3%) and tACT (+29.2%) in the biceps femoris. At faster running speeds, there were significant increases in tibialis anterior %MVC (+8.6-15.2%) and tACT (+12.7-17.0%) and rectus femoris %MVC (12.1-26.6%; swing phase). CONCLUSION: No significant environment-speed interaction effects suggested that observed muscle-activity differences between ATM and TM were due to environmental variation, ie, buoyancy (presumed to decrease %MVC) and drag forces (presumed to increase aDUR and tACT) in the water.

Comparison and reproducibility of sEMG during manual muscle testing on land and in water.

The objectives of this study were to: (1) compare the sEMG recordings from maximal voluntary contractions (MVC), and (2) examine the reproducibility of sEMG recordings from MVCs for selected lower extremity muscles derived from manual muscle testing (MMT) on dry land, and in water prior to and following aquatic treadmill running. Twelve healthy recreational male runners participated. The selected muscles were: M. quadriceps-vastus medialis (VM) and rectus femoris (RF), M. biceps femoris (BF), M. tibialis anterior (TA) and the M. gastrocnemius caput mediale (GAS) of the right leg. The MVC testing conditions were: dry land, underwater prior to (Water 1) and following an aquatic exercise trial (Water 2). For each muscle, a one-way analysis of variance with repeated measures was used to compare MVC scores between testing conditions, and the intra-class correlation coefficient (ICC) and typical error (CV%) were calculated to determine the reproducibility and precision of MVC scores, respectively, between conditions. For all muscles, no significant differences were observed between land and water MVC scores (p=0.88-0.97), and high reliability (ICC=0.96-0.98) and precision (CV%=7.4-12.6%) were observed between MVC conditions. Under MMT conditions it appears that comparable MVC sEMG values were achieved on land and in water and the integrity of the EMG recordings were maintained during water immersion. Future studies using sEMG waterproofing procedures should conduct MVC testing in water for data normalization and perform post-exercise verification of sEMG signal integrity.

Peak cardiorespiratory responses during aquatic and land treadmill exercise.

PURPOSE: Aquatic treadmill exercise has traditionally been used for aerobic training during rehabilitation; however, its ability to elicit comparable cardiorespiratory stress compared with land exercise is unclear. The purpose of this study was to investigate the cardiorespiratory (CR) responses elicited during maximal-effort protocols using an aquatic treadmill (ATM) and a land treadmill (TM). METHODS: Twenty-three college runners participated in two continuous, incremental peak oxygen consumption protocols (ATM and TM) until volitional exhaustion. For the ATM protocol, subjects were submerged in 28 degrees C water to the xiphoid process. ATM speed was increased incrementally to 206.8+/-23.1 m.min, and water jet resistance was increased 10% every minute thereafter. For the TM protocol, speed was increased to 205.3+/-22.3 m.min, and grade was increased 2% every minute thereafter. Rest between sessions was at least 48 h. Oxygen consumption (VO2), heart rate (HR), minute ventilation (VE), tidal volume (VT), breathing frequency (f), and respiratory exchange ratio (RER) were measured continuously, with peak values used for analysis. Rating of perceived exertion (RPE) was recorded immediately after each test, and blood lactate (LA) was measured 3 min afterward. RESULTS: VE and f were significantly greater in ATM versus TM; however, VO2, HR, VT, RER, LA, RPE, speed, and exercise times were similar for both protocols. CONCLUSIONS: Despite differences in VE and f, it seems that the fluid resistance created by water and jets in an ATM elicits peak CR responses comparable with those seen with inclined TM. These findings suggest that ATM running may be as effective as TM running for aerobic conditioning in fit individuals.

Decline in MHC class I expression with increasing thickness of cutaneous melanomas in standard-strain transgenic mouse models.

Major histocompatibility complex (MHC) class I proteins are required for the formation of complexes with antigenic peptides that enable cytotoxic T lymphocytes (CTLs) to recognize and lyse target cells. The frequent loss of MHC class I expression reported in human melanomas and melanoma cell lines may therefore be an obstacle to CTL-based immunotherapy. We have investigated the expression of MHC class I proteins in the cutaneous melanomas of Tyr-SV40E (C57BL/6 strain) transgenic mice in order to evaluate their potential as experimental models for immunotherapy. The SV40 large T (LT) oncoprotein, which is expressed exclusively in the melanocytic lineages of these mice, was used as a marker for flow cytometric analysis of the parenchymal (potential target) cells of 35 freshly dissociated samples from 28 primary tumours. All the tumours were ulcerated and exceeded the Breslow thickness indicative of a poor clinical prognosis in human melanoma. Using antibodies against H-2D(b) and H-2K(b) class I proteins, the LT antigen-positive cells were found to have high levels of both these MHC class I molecules in the thinnest tumours (2 mm), whereas the levels tended to decline with increasing tumour thickness. Among the tumours > 4 mm thick, five had no detectable MHC class I expression. Unexpectedly, the apparent loss of H-2D(b) and H-2K(b) proteins was observed not only in LT-positive cells but also in LT-negative cell populations. Expression of both H-2D(b) and H-2K(b) was restored in tumours derived from a class I-low melanoma cell line by treatment of the hosts with interferon-gamma. These results implicate a regulatory defect as a principal cause of the loss of MHC class I antigens, as noted by others in some human tumours, and they demonstrate that this loss is remediable, even in advanced stages of melanomas.

Efficacy and safety of dry powder fluticasone propionate in children with persistent asthma.

BACKGROUND: Flovent Diskus is a powder formulation of the inhaled corticosteroid fluticasone propionate (FP) delivered via a breath-actuated, multidose inhaler. OBJECTIVE: To determine the efficacy and safety of dry powder FP administered once or twice daily (200 microg per day) to children with persistent asthma. METHODS: Twelve-week, randomized, double-blind, placebo-controlled, multicenter trial with a 52-week, open-label extension. Children aged 4 to 11 were required to have pulmonary function 50% to 85% of predicted values. The population was stratified for baseline therapy (inhaled corticosteroid/cromolyn or bronchodilators only). After a 2-week placebo run-in, 242 patients received dry powder FP 200 microg each morning, dry powder FP 100 microg BID, or placebo for 12 weeks; 192 were rerandomized to the QD or BID regimen for an additional 52 weeks of open-label treatment. Primary endpoints were mean changes in FEV1 and morning PEF recorded at clinic visits. RESULTS: Both dry powder FP regimens significantly improved FEV1, evening PEF, and asthma symptoms at the double-blind phase endpoint (P < or = .017 compared with placebo). The BID regimen also significantly improved morning PEF and nighttime awakenings due to asthma (P < or = .005). Among patients previously treated with inhaled corticosteroids/cromolyn, improvements observed with the QD and BID regimens were similar. Patients switched from BID to open-label QD treatment showed additional improvements at week 52 generally comparable to patients who received the BID regimen during both phases. Fluticasone propionate was well tolerated for up to 64 weeks with few reports of drug-related adverse events or morning plasma cortisol abnormalities. CONCLUSIONS: Once daily dosing of dry powder FP 200 microg is an effective and convenient alternative for children whose asthma is controlled with a more frequent dosing regimen of inhaled corticosteroids.

The underwhite (uw) locus acts autonomously and reduces the production of melanin.

The mouse has provided several significant models for hypopigmentation disorders, including the major forms of albinism. Mutations at the mouse underwhite locus confer one of the most severe hypopigmentation phenotypes, similar to mutations at the pink-eyed dilution locus that is a model for type 2 oculocutaneous albinism. A melanocyte cell line established from underwhite mutant mice failed to pigment under conditions that support pigment production in wild-type melanocytes and melanoblasts from underwhite skin graft transplants failed to produce melanin in normal skin, demonstrating that the action of the gene encoded by the underwhite locus is intrinsic to melanocytes. Mice with mutations at the underwhite locus and either the pink-eyed dilution locus or the melanocortin receptor 1 locus exhibited more severe hypopigmentation than either mutation alone, suggesting that the actions of these genes are independent. These results demonstrate that the underwhite locus is a major determinant of mammalian pigmentation.

Comparative decreases in tyrosinase, TRP-1, TRP-2, and Pmel 17/silver antigenic proteins from melanotic to amelanotic stages of syngeneic mouse cutaneous melanomas and metastases.

Malignant cutaneous melanomas and metastases were taken directly from in situ lesions of genetically identical (C57BL/6 strain) Tyr-SV40E transgenic mice, and samples were analyzed by Western immunoblotting with antisera specific for the COOH terminus of each of four melanocytic proteins. These were tyrosinase, TRP-1, TRP-2, and Pmel 17/silver. Of the 13 melanomas examined, there were 5 melanotic primary tumors, 5 amelanotic primary tumors, and 3 amelanotic metastases. The melanotic tumors expressed all of the markers to some extent. In contrast, the amelanotic tumors lacked detectable levels of one, two, or three of the proteins, except for an apparently amelanotic tumor sample in which all were expressed, but in which some melanotic cells were likely to have been present. Thus, despite some variability, there is clearly a downward trend in the presence of these proteins as the tumors become amelanotic, a pigmentary change associated with ongoing malignant progression. In the amelanotic tumors, tyrosinase was most often deficient, whereas TRP-2 was most often persistently expressed. These results, obtained from melanomas of syngeneic origin, indicate that tumors in the relatively early stages of malignancy might be more responsive than later-stage tumors to immunotherapy involving an ensemble of antigenic peptides of the tested gene products. Moreover, TRP-2 peptides may be especially useful for therapeutic intervention at the later stages.

Differences in latency and inducibility of mouse skin melanomas depending on the age and anatomic site of the skin.

To determine whether the occurrence of skin melanoma is influenced by the age or the anatomic source of the skin in melanoma-susceptible transgenic mouse models, skin was grafted from donors of different ages or from different anatomic sites to a standard (lateral trunk) site in adult recipients of the same transgenic strain. In 27 grafts of neonatal body skin, melanomas arose with a significantly shorter latency than in 37 grafts of older body skin. The difference may reflect not only the larger number of extrafollicular melanocytes in a given area of neonatal skin but also their unusually high mitotic activity shortly after birth and the influence of other growing skin cells nearby. Each of these body-skin grafts usually developed a single tumor situated near the graft edge. Because maximal wound healing occurs at the edge of such full-thickness skin grafts, melanocytes near the edge would receive the highest exposure to growth factors and cytokines associated with wound healing. In contrast to these results, grafts of snout skin yielded many melanomas, each originating from melanocytes within a vibrissa follicle rather than at the graft edge. The relatively strong local tumorigenic stimulus may be attributable to intrafollicular growth factors normally involved in whisker growth. The above-described experiments support the conclusion that agents in the immediate skin environment of the melanocyte, in addition to the state of the melanocyte itself, contribute to melanoma formation.

Up-regulation of specific tyrosinase mRNAs in mouse melanomas with the c2j gene substituted for the wild-type tyrosinase allele: utilization in design of syngeneic immunotherapy models.

The expression of cell-specialization genes is likely to be changing in tumor cells as their differentiation declines. Functional changes in these genes might yield unusual peptide epitopes with anti-tumor potential and could occur without modification in the DNA sequence of the gene. Melanomas undergo a characteristic decline in melanization that may reflect altered contributions of key melanocytic genes such as tyrosinase. Quantitative reverse transcriptase-PCR of the wild-type (C) tyrosinase gene in transgenic (C57BL/6 strain) mouse melanomas has revealed a shift toward alternative splicing of the pre-mRNA that generated increased levels of the Delta1b and Delta1d mRNA splice variants. The spontaneous c2j albino mutation of tyrosinase (in the C57BL/6 strain) changes the pre-mRNA splicing pattern. In c2j/c2j melanomas, alternative splicing was again increased. However, while some mRNAs (notably Delta1b) present in C/C were obligatorily absent, others (Delta3 and Delta1d) were elevated. In c2j/c2j melanomas, the percentage of total tyrosinase transcripts attributable to Delta3 reached approximately 2-fold the incidence in c2j/c2j or C/C skin melanocytes. The percentage attributable to Delta1d rose to approximately 2-fold the incidence in c2j/c2j skin, and to 10-fold that in C/C skin. These differences provide a basis for unique mouse models in which the melanoma arises in skin grafted from a C/C or c2j/c2j transgenic donor to a transgenic host of the same or opposite tyrosinase genotype. Immunotherapy designs then could be based on augmenting those antigenic peptides that are novel or overrepresented in a tumor relative to the syngeneic host.

Selective increase in specific alternative splice variants of tyrosinase in murine melanomas: a projected basis for immunotherapy.

Melanomas tend to become less pigmented in the course of malignant progression. Thus, as proliferation increases, the tumors are decreasingly characterized by the tissue-specific phenotype of normally differentiated melanocytes. To learn whether the decline in melanization is associated with a shift from constitutive to alternative splicing of some pigment gene pre-mRNAs, melanomas were collected from Tyr-SV40E transgenic mice of the standard C57BL/6 strain. The mRNAs of the tyrosinase gene, which has a key role in melanogenesis, were analyzed by quantitative reverse transcriptase-PCR in 34 samples from 16 cutaneous tumors and 9 metastases. The cutaneous tumors included some cases with distinct melanotic and amelanotic zones, which were separately analyzed. All tyrosinase transcripts found in the melanomas were also found in normal skin melanocytes. However, the Delta1b and Delta1d alternatively spliced transcripts, due to deletions within the first exon, were specifically augmented in most of the tumors over their very low levels in skin; the exceptions were some all-amelanotic tumors in which no tyrosinase transcripts were detected. The level of Delta1b rose as high as 11.3% of total tyrosinase mRNAs as compared with 0.6% in skin; Delta1d reached 4.0% as compared with 0. 8% in skin. Expression of these splice variants was highest in the melanotic components of zonal primary tumors, relatively lower in their amelanotic components, and still lower in all-amelanotic primary tumors and amelanotic metastases. The increase in Delta1b and Delta1d transcripts may be predicted to increase the levels of unusual peptides, which could have antigenic potential in the tumors, especially in the relatively early phases of malignancy. Analyses of the alternative transcripts of other pigment genes may identify additional candidate antigens, ultimately enabling melanoma cells in all phases of the disease to be represented as a basis for immune intervention.

Placebo-controlled, double-blind study of the efficacy and safety of triamcinolone acetonide aerosol nasal inhaler in pediatric patients with seasonal allergic rhinitis.

Triamcinolone acetonide (TAA) aerosol nasal inhaler has been shown to effectively relieve the symptoms of seasonal allergic rhinitis in adults and adolescents. We conducted a study to evaluate the efficacy and safety of once-daily administration of TAA aerosol nasal inhaler in pediatric patients aged 6 to 11 years with grass seasonal allergic rhinitis. This multicenter, randomized, double-blind, placebo-controlled, parallel-group study enrolled 116 children who were treated with either TAA aerosol nasal inhaler (220 micrograms/d) or placebo once daily for 2 weeks. Patients evaluated the severity of rhinitis symptoms (nasal stuffiness, discharge, sneezing, and itching) daily according to a four-point scale (0 = absent, 1 = mild, 2 = moderate, and 3 = severe). Patients' and physicians' global evaluations of overall treatment efficacy were assessed at the end of the 2-week treatment period. Patients treated with TAA aerosol nasal inhaler had significantly greater reductions in all nasal symptom scores overall and in virtually all symptoms at the end of week 1 and week 2 compared with those in the placebo group. Both patients' and physicians' global evaluations of efficacy favored TAA aerosol nasal inhaler over placebo. This study demonstrated that once-daily administration of 220 micrograms of TAA aerosol nasal inhaler was well tolerated and effectively reduced the symptoms of seasonal allergic rhinitis in pediatric patients.

Accelerated growth of melanomas after specific immune destruction of tumor stroma in a mouse model.

Destruction of the entire stroma in a tumor could provide a stringent test of the prospects for tumor eradication in a single treatment. This possibility was investigated by experimental immune destruction of the stroma in a mouse melanoma model. Melanomas were first produced by grafting skin from transgenic C57BL/6 females of high-melanoma susceptibility to low-susceptibility transgenic males so that the malignant cells would be genetically female and the stromal cells genetically male. Subcutaneous transplant lines were then established from the melanotic and the amelanotic zones of such a melanoma and were carried in transgenic male hosts to ensure the male composition of the stroma. Thus, the male-specific H-Y histocompatibility antigen, which is ubiquitously expressed on male cells, could provide the target for an immune attack against the stroma. The transplant lines were next passaged once in transgenic females preimmunized against the H-Y antigen by having received and rejected a graft of C57BL/6 nontransgenic male skin. The antistromal immune response of these hosts did not prevent recovery of the tumors, which required a substantially prolonged latency. However, after retransplantation to nonimmunized males and females, the latency was markedly shortened from the original level. Thus, the treatment had indirectly selected for more rapidly growing tumor cells and hastened malignant progression.

Addition of anticholinergic solution prolongs bronchodilator effect of beta 2 agonists in patients with chronic obstructive pulmonary disease.

A randomized, double-blind placebo-controlled clinical trial was designed to assess the safety, efficacy, and duration of the bronchodilation resulting from the addition of 500 micrograms of ipratropium bromide (Atrovent; Boehringer Ingelheim, CT) inhalation solution to standard small volume nebulizer treatments with 2.5 mg albuterol inhalation solution. A total of 195 patients (63% men, average age 64 years) with > 10 pack-year smoking histories and stable, moderate-to- severe chronic obstructive pulmonary disease (COPD; forced expiratory volume in 1 second [FEV1] 1.02 liter, 38.8% predicted) from eight university-affiliated chest clinics in seven U.S. cities were enrolled into the study. Asthma, rhinitis, and eosinophilia were exclusions, as was daily use of > 10 mg of prednisone (or 20 mg on alternate days). There was a 2-week stabilization period during which the patients were instructed in the use of the small volume nebulizers, which they used three times daily with albuterol alone. They were asked to keep daily logs of peak flow rates, pulmonary symptoms, and additional medication usage. On their test day 1 the subjects came to the pulmonary function laboratory having been off theophylline for 24 hours and beta 2-agonists for 12 hours and performed a baseline spirometry. They then received their morning small volume nebulizer treatment of albuterol to which was added either 500 micrograms if ipratropium bromide or a saline placebo. Spirometry was repeated at 15, 30, and 60 minutes, and then hourly for 8 hours. Subjects then took home a 2-week supply of albuterol and test drug for thrice daily use in their small volume nebulizer. They were evaluated for pulmonary symptoms and adverse effects every 14 days. The 8-hour spirometry was repeated on test day 43 and finally on test day 85. Primary data evaluated were the peak increase in FEV1 and the area between the FEV1 baseline value and the 8-hour FEV1 curve. Similar calculations were made for forced vital capacity (FVC) and 25-75% forced expiratory flow (FEF25-75%). On test day 1 the peak increase in FEV1 for the ipratropium bromide + albuterol subjects was 26% greater than those on placebo + albuterol (p < 0.003). The area under the 8-hour FEV1 curve was 64% greater in those given ipratropium bromide on test day 1 (p < 0.0002). Similar increases were seen in FVC and FEF25-75%. The peak improvements in FEV1 and FVC with the addition of ipratropium bromide to albuterol were maintained on test days 43 and 85. Considering the safety and efficacy profiles of this combination, the data would suggest that ipratropium bromide inhalation solution should be considered first-line therapy for those patients with COPD requiring small volume nebulizer treatments.

Expression of plasminogen activators and plasminogen activator inhibitors in cutaneous melanomas of transgenic melanoma-susceptible mice.

The Tyr-SV40E transgenic mouse model of malignant skin melanoma has been used here to generate melanomas in genetically identical (C57BL/6) mice for analysis of the plasminogen activator (PA) system during tumor development and progression. Twenty-two melanocytic lesions were examined by in situ zymography for PA activity and by immunohistochemistry for concomitant visualization of PA proteins; these lesions encompassed 3 nevi and 19 primary melanomas ranging from melanotic through mixed tumors to amelanotic tumors. Although urokinase-type plasminogen activator (u-Pa) activity was not detected at premalignant stages, it began to appear early in tumorigenesis and became more prominent in later stages of a majority of the tumors. The activity was largely attributable to the endothelium of sprouting capillaries and to a lesser degree to granulocytes, fibroblastic cells, and occasional melanoma cells within tumors. Tissue-type plasminogen activator (t-PA) was undetectable or low in all cases. Of the inhibitors (PAI), PAI-1 was seen in endothelial and fibroblastic cells and in the extracellular matrix, whereas PAI-2 occurred in only one case and was melanoma cell associated. Eleven additional melanomas were analyzed by reverse transcription-PCR for PA expression in RNA extracts from relatively large tumor samples. These were obtained from eight primary melanomas and three metastases, again spanning melanotic, mixed, and amelanotic cases. From four of the mixed primary tumors with distinct melanotic and amelanotic zones, the respective components were propagated separately in transgenic hosts as s.c. transplants to obtain data for clearly identifiable melanotic versus amelanotic parts. u-PA and PAI-1 mRNAs were expressed in all. t-PA expression varied greatly and was notably high in several amelanotic tumors or tumor components, possibly as a result of large blood vessels, as such vessels were seen to be t-PA positive in normal tissue. The u-PA activity in sprouting capillaries may indicate a role in neoangiogenesis. Therefore, according to these mouse models, u-PA may indirectly be a potential therapeutic target against melanoma progression.

Changes in expression of putative antigens encoded by pigment genes in mouse melanomas at different stages of malignant progression.

Cutaneous melanomas of Tyr-SV40E transgenic mice (mice whose transgene consists of the tyrosinase promoter fused to the coding regions of simian virus 40 early genes) strikingly resemble human melanomas in their development and progression. Unlike human melanomas, the mouse tumors all arise in genetically identical individuals, thereby better enabling expression of specific genes to be characterized in relation to advancing malignancy. The products of pigment genes are of particular interest because peptides derived from these proteins have been reported to function as autoantigens with immunotherapeutic potential in some melanoma patients. However, the diminished pigmentation characteristic of many advanced melanomas raises the possibility that some of the relevant products may no longer be expressed in the most malignant cells. We have therefore investigated the contributions of several pigment genes in melanotic vs. relatively amelanotic components of primary and metastatic mouse melanomas. The analyses reveal marked differences within and among tumors in levels of mRNAs and proteins encoded by the wild-type alleles at the albino, brown, slaty, and silver loci. Tyrosinase (the protein encoded by the albino locus) was most often either absent or undetectable as melanization declined. The protein encoded by the slaty locus (tyrosinase-related protein 2) was the only one of those tested that was clearly present in all the tumor samples. These results suggest that sole reliance on targeting tyrosinase-based antigens might selectively favor survival of more malignant cells, whereas targeting the ensemble of the antigens tested might contribute toward a more inclusive and effective antimelanoma strategy.

Ultraviolet radiation-induced malignant skin melanoma in melanoma-susceptible transgenic mice.

A new mouse model of UV radiation-induced melanoma is described. Unlike previous models, melanoma induction requires only short-term irradiation, does not require the application of chemical carcinogens, and does not cause any other tumors. The model takes advantage of the fact that Tyr-SV40E (C57BL/6 strain) transgenic mice are all melanoma-susceptible, and that different inbred lines are susceptible to different extents. Four-day-old mice of a moderately susceptible line (line 9 transgenic homozygotes) were exposed for 20 min/day to 328 mJ/cm2 to UVB (280-320 nm wavelength, comprising 70% of the total irradiance) for up to 4 consecutive days. Melanocytic lesions resembling macules, nevi, or early melanomas gradually appeared in the irradiated mice that were not seen in unirradiated transgenic controls of similar age. To afford ongoing observation beyond the short life span of line 9 homozygous mice, skin samples containing a total of 26 selected lesions were grafted at 20 weeks after UV radiation to longer-lived unirradiated hosts of transgenic line 12, in which melanoma susceptibility is low. Ten lesions in the grafts became melanomas; all melanomas had ulcerated and two had metastasized. At the stages examined, all the tumors were deeply melanotic. The remaining 16 lesions were still indolent when the experiment was terminated at 57 weeks post-UV radiation. The present protocol lends itself to variations in the choice of transgenic line, the age of the treated mice, and the intensity and duration of ultraviolet light; appropriate combinations of these variables would be expected to yield melanomas in relatively long-lived transgenic mice without skin grafting. The new model provides an opportunity to determine the melanoma action spectrum, to characterize at the molecular level the melanomas induced by ultraviolet light in comparison with those of other origins, and to investigate in vivo the photoprotective role of melanin.

A double-blind study of the efficacy of nedocromil sodium in the management of asthma in patients using high doses of bronchodilators.

The effects of nedocromil sodium were assessed in 110 patients with asthma who experienced asthma symptoms despite the use of high doses of inhaled bronchodilators. During the baseline period, antiinflammatory agents were not permitted, and patients were treated with inhaled beta-agonists on an as-needed basis. Patients who required 12 or more puffs of albuterol and experienced continuing asthma symptoms for 7 of the 14 baseline days were randomized to treatment groups. Subjects received either nedocromil sodium (4 mg) or placebo four times a day for 10 weeks. Statistically significant (p < 0.05) between-treatment differences (weeks 3 to 10), favoring nedocromil sodium, were determined for the asthma summary score, daytime asthma severity, asthmatic cough, morning peak flow rates, reduction of as-needed bronchodilator use, physician's assessment of asthma severity, and patient and physician opinions of treatment effectiveness. By trial end (week 10), sleep difficulty caused by asthma decreased 29% in the nedocromil sodium group and 4% in the placebo group (p = 0.006). Nedocromil sodium was well tolerated and improved asthma control while reducing the inhaled bronchodilator load of these patients with moderately severe asthma.

Asthma ski day: cold air sports safe with peak flow monitoring.

The Colorado Asthma Ski Day, an annual cross-country and alpine skiing event, encourages children with asthma to participate fully in outdoor winter sports. Since cold air and exercise can trigger bronchospasm, we examined the peak expiratory flow rates of 80 children who attended Asthma Ski Day 1992 or Asthma Ski Day 1993 to establish a safety profile for this event. Peak expiratory flow rates were measured prior to skiing, at lunchtime, and at the end of the day's activities. We asked the children to pretreat with their regular medications, as prescribed by their physicians, to use their bronchodilator inhalers p.r.n., and to report to our medical station if an episode of acute asthma occurred. The average age of the participants was 9.5 years, and the average baseline daytime peak flow rate was 100.03% of predicted. The average percent change in peak flow rates during the day was an increase of 5.00%. Our results demonstrate that with medical supervision, peak expiratory flow rate monitoring, and properly administered medications, peak flow rates can be stabilized and even improve during cold-weather exercise to an extent that safety concerns need not restrict children with asthma from engaging in exercise or cold-weather sports. The Colorado Asthma Ski Day can serve as a model event for other organizations that want to promote outdoor activities for children with asthma.